3-acyl amino-4-carboalkoxyamino thiophenes



Patented Apr. 4, 1950 3-ACYL AMINO-4-CARBOALKOXYAMINO THIOPHENES Lee C. Cheney, Syracuse, N. Y., and John Robert Piening, Detroit, Mich., assignors to 'Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Original application December 23,

1944, Serial No. 569,640. Divided and this application April 8, 1946, Serial No.660,405

4 Claims.

This invention relates to the preparation of new compounds useful as intermediates for the synthesis of pharmaceuticals particularly compounds possessing biotin and possible anti-biotin activity.

This application is a division of our application Serial No. 569,640, filed December 23, 1944, now Patent No. 2,466,004, issued April 5, 1949, and relates more particularly to the preparation of 3-acylamino-4-carboalkoxyamino-2-w-R-alkyl thiophenes. These new compounds are prepared by reacting 3-acylamino-2-w-R-alkyl-4-thiophene carboxylic acid azides with alcohols according to the following diagram.

In the above diagram COR," is an organic carboxylic acid acyl radicaL'R' is a lower alkyl (including lower cyclo alkyl) or aryl-substituted lower alkyl, R2 is a radical of the class --COOH,

alkoxy, aralkoxy and aryloxy and n is an integer from 1 to 8.

The preparation of the starting materials of this divisional application'is described in our parent application Serial No. 569,640 and our copending application Serial No. 569,639, filed December 23, 1944, now Patent No. 2,443,598, issued June 22, 1948.

The following examples illustrate the invention.

Example 1 3 benzoylamz'no-4-carbethoxy-2-thiopheneva ler c acid.A cooled solution of 2.71 g. (0.01 mole) of 3-amino-4-carbethoxy-2-thiophenevaleric acid in 25 ml. of dry chloroform is treated with 1.4 ml. of benzoyl-chloride. The mixture is protected by a calcium chloride tube and refluxed on the steam bath for 24 hours. Following removal of solvent by steam distillation, the residual brown oil is dissolved in ether, and the ether solution is extracted-thrice with 5% sodium bicarbonate solution. The combined alkaline extracts are cooled, acidified to Congo red with dilute hydro-. chloric acid and extracted twice with ether. Combined ether extracts are dried with anhydrous sodium sulfate, the ether is evaporated and the residue is shaken with 200 m1. of petroleum ether (B. P.- 3560 C.) for the removal of benzoic acid. The resulting light tan solid is filtered.

' more precipitate forms.

*- 30- ml. of water.

oooolm 110 wnmooon Anal.--Calcd. for C19H21O5NS: C, 60.77; H, 5.63. Found: C, 60.70; H, 5.53.

3 benzoylaminoaZ-A-carborybutyl -'4 thiophenecarboxyl c acid hydrazide.A mixture of 1.10 g. (0.00293 mole) of-3-benzoylamino-4-carbethoxy-Z-thiophenevaleric acid and 0.308 g. (0.00308 mole) of potassium bicarbonate is warmed with 25 ml. of 50% alcohol until solution is complete. Solvent is distilled at reduced pressure, leaving the potassium salt which is desiccated overnight in vacuo over phosphorus pentoxide. This dry salt is dissolved in 10 ml. of warm absolute alcohol, treated with 10 ml. of dry benzene and 2 m1. of hydrazine hydrate, protected by a calcium chloride tube and refluxed on the steam bath for 16 hours under a Soxhlet extractor containing 25g. of anhydrous calcium sulfate in its thimble. Solvent and excess hydrazine hydrate are distilled at reduced pressure, leaving a flufiy mixture consisting mainly of the potassium salt of .3-benzoylamino-2-A carboxybutyl-4-thiophenecarboxylic acid hydrazine along with some potassium salt of unchanged 4-carbethoxy compound; The mixtureis dissolved in A yellow aqueous solution is obtained which can be mixed with inert water immiscibleorganic solvent, such as. ether, and then acidified with a lower aliphatic carboxylic acid, such as acetic or propionic acid, whereby unchanged starting material goes into-the ether solution but the desired 4-thiophenecarboxylic acid hydrazide is insoluble in the ether as well as the aqueous phase andcan be filtered ofi. Thus, the yellow solution is covered with 30 ml. of ether and is made almost neutral to litmus with 5% hydrochloric acid solution. I The-ether of the resulting mixture serves to dissolve unchanged 4- carbethoxy starting material. The mixture is acidified with 10% acetic acid solution until no The mixture is stirred and cooled, and the white crystalline solid filtered off and dissolved in a minimum of boiling water, digested with activated charcoal, filtered and cooled. The fine, white crystals which separate 3 weigh 0.95 g. (90% yield), and melt at 140-141 C. The formula of the compound is Anal.Calcd. for C17H19O4N3S: C, 56.49.; H, 5.30. Found: C, 56.40; H, 5.57.

In this example water is liberated When the hydrazine hydrate reacts. The water liberated is quickly carried into the refluxing vaporsand by them into contact with the anhydrous calcium sulfate in the thimble and thereby removed from the reactants. The mixture of. dry benzenewith alcohol facilitates the removal of the water. Such procedure for removing water is important, since its use almost doubles the yield of hydrazide over that obtained when using alcohol in the absence of the benzene and the anhydrous calcium sulfate.

3 benaoylamino" 2 A carliorrybutyl 4 thiophenecarboxylic acid dz'icle.--After' dissolving 0.625 g. (0.00173 mole) of 3-benzoylamino-2-A- carboxybutyl-4-thiophenecarboxylic acid hydrazide in ml. of glacial acetic acid by the application of heat, the we'll-stirred solution is cooled in an ice bath and treated with 0.2 ml. of concentrated hydrochloric acid. To the solid white precipitate thus formed is then. added dropwise during five minutes a solution of 0 .130 g. (0100188 mole) of sodium nitrite in 8.5 ml. or water, and 1.5 ml. of water is used as a rinse. The hydrazide completely dissolves and the azide soon begins to precipitate. After one hour 25* of water is added dropwise to street complete precipitation and the mixture is stirred at o o. for an additiorial hour. The white a'zide is collected by suction, washed thoroughly with ice water and desiccated in vacuo over phosphorus pentoxide. It weighs 0156- g. (87%- yield) and decomposes at 99=100 C. Its formula Anal.-Calcd. for CivHmdsNiS: 6,5 1.83; H, 4.33. Found: C, 55.11; H, 4.53.

3 benzoylamin'o 4 carbethoryamino 2 ilu'opheneoalerzc acid-A mixture of 0.51 g. of 3- benzoylamino 2' A carboxybutyl 4 thiopheneoarboxylic acid azide and 50 ml. of absolute alcohol is rotected by a calcium chloride tube and refluxed on the steam bath for 17 hours. Ex-

alcohol is distilled at reduced pressure, the solid residue consisting mainly of the desired 4- carbethoxyami'no derivative is dissolved in ether and the ether solution is extracted twice with 5% sodium bicarbonate solution. Acidification of the combined alkaline extracts with dilute hydrochloric acid precipitates 0.49 g. of light brown solid which is collected and recrystallized from dilute alcohol toyieIdOAl g. (76.7%) of colorless crystals, P. 156.5 '157.5 CI, having the formula NH-GOOCaHs -O-=NH- 0 00611: HO. '(CH:)4C'OOH Anal-Calcd. for ClQH2205N2S! c, 53.44; H. 5.68. Found: C, 58.88; H, 5.72.

Example 2 Ethyl 3 benzoylamz'no 2 'y phenozrypropyl 4 thiophenecarbomylate.-To a. warm solution of 141g. (0.046 mole) of 3-amino'-4.-carbethoxy-2- 'y-phenoxypropylthiophene, M. P.. 56-57 C. in ml. of glacial acetic acid is added 100 ml. of a saturated solution of sodium acetate. The well- .stirred suspension is cooled in an ice bath and 8 ml. (9.7 g.) (0.069 mole) of benzoyl chloride is added dropwise. Lumps of solid soon separate. After stirring. for 40 minutes the suspension is filtered and washed: with ice water. The granular product is dissolved in 180 ml. of hot glacial acetic acid, treated with 70 ml. of a saturated solution of. sodium acetate, cooled in ice and again treated with 8 ml. of benzoyl chloride. As soon as the suspension solidifies the ice bath is removed, 50 ml. of water is added and the mixture is stirred at room temperature for 3.5 hours. Then 100 ml. of water is added and the suspension is cooled, filtered, washed with cold water and desiccated in vacuum over P205. Crystallization from alcohol following Darco treatment produces-1 5173. (8'3 yield) of line ivory crystals, M. P. 97-98 C. A sample of the compound is recrystallized from alcohol (Darcol as colorless needles, ML F. 98-99 C.

Allah-Coded. for CzsHzsOsNS: C; 6-7.5; H, 5.55. Found: C, 67.38"; H, 5.91.

Its formula is ll no i lc Holcomb 3 benzoylamino 2 'y phenozcypropyl 4 thz'ophenecarb'ozrylic acid hydrazide.A mixture of 14.6 g. (0.0357 mole) of ethyl 3-benzoylamino- 2-' -phenoxypropyl-4-thiophenecarboxylate, 1 0 0 ml. of absolute alcohol and 25 ml. of 85% hydrazine hydrate is refluxed for 16 hours on. the steam bath. During the night white crystals separate from solution. After removal. of excess hydrazine by distillation at reduced pressure, the crystalline mass is boiled with about 700 ml. of absolute alcohol, cooled in an ice-salt bath and. filtered. Following desiccation the fine lustrous crystals melt at 186-.5187.5 C. The yield is 13.1 g. or 93% of the theoretical.

Anal.--Calcd. for CziHzioaNsSt C, 63.8; H, 5.34. Found: C, 63.77; H, 5.29.

Its formula is 3 benzoylamino 2 'y phenomypropyZ-4-thiophene'carb'ozcyli'c acid azide.After dissolving 7.91 g. (0.020 mole) of the corresponding hydrazide, M. P. 18654875 C'., in 200 ml. of glacial acetic acid by the application of heat, the well-stirred solution is cooled in an ice bath and treated with 2.25 ml. of concentrated HCl. A fine, white precipitate of the hydrochloride forms immediately. Then a solution of 1.50 g. (0.0217 mole) of sodium nitrite in 35 ml. of water is added dropwise during 7 minutes and the reaction mixture is stirred in the ice bath for 2.3 hours. Following filtration the white, finely crystalline azide is washed with ml. of ice water and dessicated overnight in vacuum over P205; decomposition point, 108-109 C.; weight, 7.1 g.

'aitobilb? I "lanai-calm. for C21H13O3N4S: o, 61.9; 4.45; N, 13.79. Found: C, 62.30; H, 4.24; N, 13.78.

3 benzoylamino-e!-carbethoxyamino-2-y-phenoM/WWl/l-thiophena-One gram (0.00246 mole) of 3-benzoylamlno 2 'y phenoxypropyl-4-thiophenecarboxylic acid; azide, decomposition point 108-109 C., is refluxed with 100 ml. of absolute alcohol for five hourswhile a calcium chloride tube excludes moisture. .After concentration to a-lvolurne of 45 ml., water is added to make the total volume 125ml. Cooling in an ice-salt bath, filtration and dessication yield 1.04 g. (quantita tive yield) of fine. white needles, M. P. 144-145 C. Recrystallization of a sample from alcohol produces silky needles, M. P. 146-146.5 C.

Anal-Calcd. for C23H2404N2S: C,-65.1; H,5.70. Found: C, 65.31; H,.5.81.-

Its formula is II no Example 3 Ethyl 3-benzoylamino-2-7-benzyZomypropyl-4- thiophenecarbowylate. A mixture of 2.79 9. (0.00875 mole) of 4-carbethoXy-S-amino-2-'y-benxyloxypropylthiophene, 13 ml. of dry chloroform and 1.2 ml. of benzoyl chloride is refluxed on the steam bath for 17 hours. The chloroform is removed by steam distillation. The water is poured from theoil after; cooling. The oil is dissolved in alcohol and is given a treatment with Darco. The alcohol solution is concentrated after filtering from Darco and is treated with hot water until a faint turbidity remains. When cool, an oil separates out. Addition of a large volume of water precipitates more oil. After scratching and cooling for several hours the product begins to crystallize, yielding a'tan material which is collected, dried and weighed. 'The weight of crude material is 3.4 g., yield 92%, M. P. 60 C. A'

3 benzoylamino 2- -ben2yZom2lpT0mZ-4-thiophenecarboxylz'c acid hydrazida-A mixture of 2.96 g. (0.007 mole) of 4-carbethoxy-4-benzoylamino-2-Y-benzyloxypropylthiophene, 20 ml. of absolute alcohol-and 5 ml. of 85% hydrazine hydrate is refluxed on the steam bath for 16 hours.

The solution is' cooled in an ice bath. After several hours a fiocculent mass of crystals are formed. These are collected and dried. Weight,

0.64 g., M. P. 116-117 C. The filtrate is warmed and diluted with alarge volume of water. Cooling and stirring produces further crystals of crude hydrazide. Weight, 1.89 g.

Anal. Calcd. for C22H2303N3S: N, 10.26%. Found: N, 10.07%.

. forms.

farms.

, r 1 s f I 3 ,benzoyZamino-Z-' -benzyloscypropyl-4-thiophen'ecarbowylic aciddzz'da-A solution of 2.43 g. (0.00594 mole) of 3 benzoylamino-2-y-benzyloxypropyl-4-thiophenecarboxylic acid hydrazide madein 25 ml. of glacial acetic acid. The solution is cooled in an ice bath until the acetic acid crystallizes. The ice bath is removed and the acetic acid is allowed to melt again before adding 0.67 ml.. of concentrated HCl. The flask is returned to the ice bath and while the solution is being stirred vigorously it is treated with a solution of 0.446 g. (0.00646 mole) of NaNO-.' in 10.5 ml. of water. i The addition-is dropwise over a period of three minutes. The solution becomes turbid but no crystals form. .After stirring for an hour, water is added-dropwis'e until a white turbidity remains. This disappears and a dark oil- More water is added in this manner until finally white crystals begin to form. The mixture is stirred another hour before filtering off the crystals- These are washed thoroughly with ice water and then are dried over P205 in a vacuum dessicator for 20 hours. Weight of crudeazide is 2.15g., yield 86%, M. P. 6264C.

Itsformula is ooN. ism-000015 '1 C 3-benzoylamino 2-7-ben2yl0xyproqryl -4 -,-v carb ethoxyaminothiophene.-A solution of 2, g. (0.00475 mole) of azide in 30 ml. of absolute alcohol is refluxed on the steam bath for '7 hours. The brown solution'is treated with Darco and then filtered. A pale yellow solution results. This is" concentrated to /g volume. Water, is added until a turbidity remains. Cooling and stirring produce no crystals. More water is added andan oil percipitates from the milk-like suspension. Cooling in an ice bath harden's the oil. More wateris added until about 5 times the original volume of alcohol has been added. Stir-' ring causes crystals to form. After standing overnight in the ice box the soft crystals are filtered and dried. Weight, 1.87 g., yield 8%, M. P. of crude material C. The product is crystallized from dilute alcohol (2 vols. alcohol to 1 of water). Beautiful white needles are obtained which melt at 88-89 C. Weight, 1.34. g. A sample is recrystallized and melts at 90-91 C.

Anal.Calcd. for C24H2BO4N2S: N. 6.38%. Found: N, 6.41%.

Its formula is NBC 0 002m oc-NH-o 00.11,

The 3-amino-4-carbethoxy-2-thiophenevaleric acid used in Example 1 as a starting material can be made from ethyl 3-amino-4-carbethoxy-2- thiophenevalerate of M. P. 43-44" C. as described in our Patent No. 2,443,598, aforesaid. This 44 C. melting compound is prepared from the oxime of ethyl 4-carbethoxy-3-keto-2-tetrahydrothiophenevalerate by treatment of a dry ether solution of the latter with dry hydrogen chloride gas, converting the amine hydrochloride to the amine with alkali bicarbonate, and finally partially hydrolyzing the amine to the mono-ester. The oxime mentioned is made, from ethyl 4-carbethoxy-3-keto 2 tetrahydrothiophenevalerate and hydroxylamine hydrochloride by the known procedure" for producing'o'ximesfrom their corresponding ketones. The B-keto compound is, in its turn, made from the action of dry sodium ethylate in dry benzene on p-carbethoxyethyla,w'-dicarbethoxyamyl sulfide of formula o0 CH2 COOG2H5 (1H2 (I /H( OH2)4COOC2H5 The cyclic 3-keto compound can be purified by way of its copper chelate salt. v

The above mentioned sulfide is obtainable by reacting an alkaline solution of ,s-mercaptoproe picnic acid with a-ohloropimelic acid. The a-- chloropimelic acid is obtained by first reacting a solution of sodio ethyl malonate with ethyl An-chlorovalerate and 'hydrolyzing the tri-ester obtained into A-carboxybutylmalonic acid,- thereafter using sulfuryl chloride to convert the butylmalonic acid compound to A-carboxybutylchloromalonic acid which can be decarboxylated by heat to a-chloropimelic acid of formula" which are. nevertheless within the scope oi the invention, will occur to those skilled in the art. For example, in the first step wherein the 3-amino group is converted to an amide group, any suitable organic carboxylic acid acylating agent may be used, such as 'acetyl chloride, acetic anhydride, phenyl acetyl chloride, naphthoyl chloride as well as be'nzoyl chloride.

Q where the alkyl chain, -CnH2'n+-, consists Instead of using ethylalcohol to convert the azide to its carbethoxy-amino derivative, one may use any other lower alkyl'lor cycloalkyl) alcohol or aryl substituted lower alkyl alcohol such as benzyl'alcohol or phenyl ethyl alcohol.

What we claim as our inventionis:

'1. A compound of the formula NHoooR'" I of from 1 to 8 carbon atoms, where R' 'CO is an organic carboxylicacid acyl radical, R is a member of the class consisting of lower alkyl, lower cycloalkyl and aryl substituted lower alkyl and R2 is a member of the class consisting of -COOH, alkoxy, aralkoxy and aryloxy v 2. A compound of the formula NHOOOCzHs o-0Nn c0-otH-,' H %(OH)4-GOOEi 3. A compound of the formula NHCOOCiH (|I]C-NH-C 006115 H ocH,' 3 o-odn s Y *4. A compound of the formula smooch:

C-CNH-COCiH5 'H C(CH2)a-O'CH2CuHs 1 LEE C. CHENEY.v

JOHN ROBERT PIEN ING.

REFERENCES CITED The following references are of record in the file of this patent: r

' UNITED STATES PATENTS Name 1 Date Schnider -r Mar. 11, 1947 Number 

1. A COMPOUND OF THE FORMULA 